Influence of exogenous melatonin on catecholamine levels in postmenopausal women prior and during oestradiol replacement

OBJECTIVE: In young individuals melatonin administration reduces circulating norepinephrine. Some effects of melatonin are reduced in elderly women and are modulated by gonadal steroids. Accordingly, the influence of melatonin on catecholamine levels was investigated in postmenopausal women without and with oestradiol replacement. DESIGN: Prior to and after 2 months of transdermal oestradiol (50 microg/day), women were studied on two consecutive days, on which they received placebo or 1 mg of melatonin orally in a randomised and double-blind fashion. PATIENTS: Fourteen healthy postmenopausal women. MEASUREMENTS: Resting levels of epinephrine and norepinephrine and their responses to both a cold stimulus, performed by placing a hand in a basin of water and ice for 2 minutes, and to 10 minutes of upright position (upright test). RESULTS: Prior to oestradiol, melatonin did not modify baseline or stimulated catecholamine levels. In contrast, during oestradiol, melatonin tended to reduce, although not significantly, baseline norepinephrine levels (P = 0.053), and significantly reduced peak values (P = 0.0061) and integrated norepinephrine response (P = 0.0076) to the cold stimulus. Responses of norepinephrine to the upright test were not modified, while those of epinephrine were increased (P = 0.042). During, but not prior to oestradiol replacement, modifications induced by melatonin (melatonin day-placebo day) in the norepinephrine response to the cold (r2 = 0. 457; P = 0.0079) and the upright (r2 = 0.747; P = 0.0001) tests were linearly and inversely related to the responses of the placebo day. CONCLUSIONS: Melatonin does not modulate adrenergic activity in postmenopausal women without hormone replacement therapy. Oestradiol replacement restores the capability of melatonin to modulate adrenergic activity, particularly the norepinephrine response to stimuli.     

Melatonin effect on plasma adiponectin,leptin, insulin,glucose, triglycerides and cholesterol in normal and high fat–fed rats

Abstract: Melatonin effect on body weight progression, mean levels and 24‐hr pattern of circulating adiponectin, leptin, insulin, glucose, triglycerides and cholesterol were examined in rats fed a normal or a high‐fat diet. In experiment 1, rats fed a normal diet were divided into two groups: receiving melatonin (25 μg/mL drinking water) or vehicle for 9 wk. In experiment 2, animals were divided into three groups: two fed with a high‐fat diet (35% fat) and melatonin (25 μg/mL) or vehicle in drinking water for 11 wk, while a third group was given a normal diet (4% fat). At the end of experiments, groups of eight rats were killed at six different time intervals throughout a 24‐ hr period. Melatonin administration for 9 wk decreased body weight gain from the 3rd wk on without affecting food intake. A significant reduction in circulating insulin, glucose and triglyceride mean levels and disrupted daily patterns of plasma adiponectin, leptin and insulin were observed after melatonin. In high fat–fed rats, melatonin attenuated body weight increase, hyperglycemia and hyperinsulinemia, as well as the increase in mean plasma adiponectin, leptin, triglycerides and cholesterol levels. The high‐fat diet disrupted normal 24‐ hr patterns of circulating adiponectin, insulin and cholesterol, the effects on insulin and cholesterol being counteracted by melatonin. Nocturnal plasma melatonin concentration in control and obese rats receiving melatonin for 11 wk attained values 21–24‐fold greater than controls. The results indicate that melatonin counteracts some of the disrupting effects of diet‐induced obesity in rats.     

Melatonin: a major regulator of the circadian rhythm of core temperature in humans.

The circadian rhythm of core body temperature (BTc), with maxima during the day and minima at night, is normally coupled with the sleep-wake cycle. Pineal melatonin secretion occurs contemporaneously during the nighttime hours and is mediated by the activation of beta-adrenergic receptors during darkness. The hypothesis that nocturnal melatonin secretion may be involved in the regulation of the human circadian BTc rhythm was examined. The temporal relationship between melatonin and the circadian BTc rhythm was characterized in 12 young women, normally entrained to the light-dark cycle. Melatonin levels were manipulated through the administration of exogenous melatonin (2.5 mg, orally) during the daytime (n = 6) or suppression of endogenous nocturnal melatonin secretion by the beta-adrenergic antagonist atenolol (100 mg; n = 6) in double blind placebo-controlled experiments conducted during 2 consecutive days. Serum melatonin levels and BTc were monitored at 20- and 10-min intervals, respectively. In a nightshift worker the temporal relationship between the circadian rhythm of melatonin and BTc was investigated before and after entrainment to a reversed wake-sleep cycle. Our data show that in normally entrained subjects, the time course and amplitude of nocturnal melatonin secretion were temporally coupled with the decline of BTc (r = 0.97; P less than 0.00001). The same occurred in the nightshift worker, both during the dissociation and after entrainment to the reversed sleep-wake cycle. Compared with placebo, administration of melatonin significantly reduced daytime BTc (P less than 0.01), and the suppression of melatonin (by atenolol) attenuated the nocturnal decline of BTc (P less than 0.01). Cosinor analysis showed that the amplitude of the circadian BTc rhythm was reduced by about 40% in response to both daytime melatonin administration (P less than 0.05) and nocturnal melatonin suppression (P less than 0.02). In conclusion, circadian rhythms of melatonin and BTc are inversely coupled. The demonstrated hypothermic properties of melatonin are accountable for the generation of at least 40% of the amplitude of the circadian BTc rhythm. Manipulation of melatonin levels might be clinically useful to resynchronize the BTc rhythm under conditions of BTc rhythm desynchronization.     

Time-dependent effects of melatonin on immune measurements in male Syrian hamsters

Abstract: Adult, male Syrian hamsters received daily subcutaneous melatonin (25 μg) injections or vehicle injections at 08:00 or 17:00 hr for 11 weeks. Body weights were measured weekly throughout the experiment and testes weights, spleen weights, and serum was collected at the end of the experiment. The spleens were sectioned and immunocytochemically analyzed for immunoglobulin G and serum levels of interferon-gamma, interleukin-2, and interleukin-4 were determined in heterologous mouse assays. Melatonin injections at 17:00 hr, but not at 08.00 hr, increased body weights, decreased testes weights and serum testosterone levels, and had no effect on immunoglobulin G content in the spleen. Likewise, melatonin injections at 17:00 hr, but not at 08:00 hr, increased serum interferon-gamma levels, had no effect on interleukin-2 levels, and appeared to increase interleukin-4 levels. Since melatonin injections at 08:00 hr were ineffective in altering immune measurements and correlations between reproductive measures and immune measures were high, the most parsimonious explanation for these results is that melatonin injections at 17:00 hr depressed reproductive hormone levels and these depressed levels altered immune measures.     

Melatonin increases activities of glutathione peroxidase and superoxide dismutase in fetal rat brain

Melatonin is a powerful scavenger of oxygen free radicals. In humans, melatonin is rapidly transferred from the maternal to the fetal circulation. To investigate whether or not maternal melatonin administration can protect the fetal rat brain from radical-induced damage by increasing the activities of antioxidant enzymes, we administered melatonin to pregnant rats on day 20 of gestation. Melatonin (10 mg/kg) was injected intraperitoneally at daytime (14:00 hr) and, to remove the fetuses, a laparotomy was performed at 1, 2, or 3 hr after its administration. We measured the melatonin concentration in the maternal serum and in fetal brain homogenates and determined the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in fetal brain homogenates. Melatonin administration markedly increased melatonin concentrations in the maternal serum and fetal brain homogenates, with peak levels achieved 1 hr after melatonin administration (serum: 538.2+/-160.7 pM/mL; brain homogenates: 13.8+/-2.8 pM/mg protein). Between 1 and 3 hr after melatonin administration, GSH-Px activity in fetal brain homogenates increased significantly (P<0.01). Similarly, SOD activity increased significantly between 1 and 2 hr after melatonin administration (P<0.01). These results indicate that melatonin administration to the mother increases antioxidant enzyme activities in the fetal brain and may thereby provide indirect protection against free radical injury. Thus, melatonin may potentially be useful in the treatment of neurodegenerative conditions that may involve excessive free radical production, such as fetal hypoxia and preeclampsia.     

Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy

OBJECTIVE: Several effects of melatonin are modulated by gonadal steroids and are reduced in ageing women. Administration of melatonin reduces internal carotid artery pulsatility index (PI), and blood pressure in young individuals. Whether these effects are conserved in postmenopausal women and are influenced by hormone replacement therapy (HRT), was herein investigated. DESIGN: Randomised, double-blind placebo controlled study. PATIENTS: Twenty-three postmenopausal women of which 11 were unreplaced with HRT and 12 on the oestrogenic phase of continuous transdermal estradiol (50 microg/day) plus cyclic medroxyprogesterone acetate (5 mg/day x 12 days every 28 days). MEASUREMENTS: Internal carotid PI, by colour Doppler, and supine blood pressure were evaluated 90, 180 and 240 minutes following the oral administration of melatonin (1 mg) or placebo. Levels of nitrites/nitrates (NOx), the stable derivatives of nitric oxide, were also evaluated in samples collected 90 minutes following the administration of placebo or melatonin. RESULTS: In women not on replacement therapy melatonin was ineffective. In HRT-treated women, melatonin reduced internal carotid artery PI (P = 0.005). The effect was maximal within 90 minutes, and maintained for at least 240 minutes, with melatonin levels in the nocturnal physiological range. Systolic and diastolic blood pressures were reduced of 8 mmHg (P = 0.038) and 4 mmHg (P = 0.045), respectively, while NOx levels were significantly increased (P = 0.024). CONCLUSIONS: The circulatory response to melatonin is conserved in postmenopausal women with but not without hormone replacement therapy. Maintenance of the cardiovascular response to melatonin, may be implicated in the reduced cardiovascular risk of postmenopausal women with hormone replacement therapy.     

Analysis of the daily changes of melatonin receptors in the rat liver

Melatonin membrane (MT1 and MT2) and nuclear (RORα) receptors have been identified in several mammalian tissues, including the liver. The mechanisms regulating hepatic melatonin receptors are yet unknown. This study investigated whether these receptors exhibit daily changes and the effects of melatonin on their levels. Our results show that mRNAs for MT1/MT2 receptors exhibit circadian rhythms that were followed by rhythms in their respective protein levels; the acrophases for the two rhythms were reached at 04:00 and 05:00 hr, respectively. Pinealectomy blunted the rhythms in both mRNAs and protein levels. In contrast, mRNA and protein levels of nuclear receptor RORα increased significantly after pinealectomy. The cycles of the latter receptor also exhibited circadian rhythms which peaked at 03:00 and 03:45 hr, respectively. Melatonin administration (10–200 mg/kg) increased in a dose‐dependent manner the protein content of MT1/MT2 receptors, with no effects on RORα. Lunzindole treatment, however, did not affect melatonin receptor expression or content of either the membrane or nuclear receptors. Together with previously published findings which demonstrated the intracellular distribution of melatonin in rat liver, the current results support the conclusion that the circadian rhythms of MT1/MT2 and RORα receptors are under the control of the serum and intracellular melatonin levels. Moreover, the induction of MT1/MT2 receptors after the administration of high doses of melatonin further suggests that the therapeutic value of melatonin may not be restricted to only low doses of the indoleamine.     

Effects of administration of 17beta-oestradiol on serum leptin levels in healthy postmenopausal women

OBJECTIVE: Women have higher leptin levels than men at a certain degree of adiposity. The role of oestrogens in the regulation of serum leptin levels remains inconclusive. The aim of the present study was to investigate the effect of unopposed oestrogen replacement therapy, during two months, on serum leptin levels in postmenopausal women. DESIGN: A double-blind, placebo-controlled, randomized study. SUBJECTS: Twenty-five healthy postmenopausal women were studied (mean (+/- SD) age: 52.9 +/- 2.7 years, range of age: 48.7-57.4 years; mean body mass index (BMI): 26.4 +/- 4.2 kg/m2, range of BMI: 21.0-39.0 kg/m2). Twelve of these women were treated with 2 mg 17beta-oestradiol daily, and 13 postmenopausal women received placebo. MEASUREMENTS: Before and at the end of a 2-month study period, anthropometric and bio-electrical impedance measurements were performed, and fasting blood samples were taken, to determine serum levels of sex hormones and leptin. RESULTS: During the 2-month study period, body weight had increased significantly in the placebo group compared with the treatment group, but no significant changes were observed in percentage of body fat or the amount of body fat in kg between the groups. Following administration of 17beta-estradiol, the median leptin level increased from 17.6 microg/l to 24.1 microg/l after 2 months (P = 0. 008 compared with baseline). This increase was significantly different from the placebo group (P = 0.019), which showed no change in circulating leptin levels. CONCLUSION: This study demonstrates that unopposed oestrogen replacement therapy during 2 months in postmenopausal women slightly, but significantly, increases total serum leptin levels. This observation suggests a role for oestrogens in the regulation of leptin.     

Melatonin and the coding of day length in male Syrian hamsters

Two experiments investigated the response of the pituitary-gonadal axis of pinealectomized male Syrian hamsters to programmed systemic administration of melatonin. In the first experiment, castrated male Syrian hamsters were housed in a short photoperiod (8L:16D) and maintained on subcutaneous testosterone implants for 7 weeks. These males were then pinealectomized or sham-pinealectomized and their testosterone capsules removed. Daily infusions of melatonin 250 ng/infusion) or its vehicle were administered for 3 weeks; infusion duration was long (11 or 12 hr) or short (6 hr). Measurement of serum luteinizing hormone (LH) following this 3-week period indicated that long-duration melatonin infusions mimicked short-day conditions (LH levels were low), but short-duration infusions did not (LH levels were significantly elevated). In the second experiment, pinealectomized, gonadally intact males were housed in a 12L:12D photoperiod and injected once daily with melatonin or its vehicle, either 3 or 5 hr after dark onset for 11 weeks. These times were chosen to coincide with the light:dark cycle phase that according to published reports is optimally responsive to exogenous melatonin for the induction of short-photoperiodic effects. Melatonin injections did not induce gonadal regression in pinealectomized hamsters. Melatonin and vehicle-treated males responded similarly; their testis widths and serum testosterone levels were not significantly different at the end of the experiment. These results support the hypothesis that the duration of melatonin secretion each night is an important variable in conveying photoperiodic information, but that the circadian phase during which melatonin is present is not.     

Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy

Serum melatonin concentrations were studied in normal pregnant women and in women with several types of pathologic pregnancies, e.g., twins, preeclampsia or intrauterine growth retardation (IUGR). Blood samples were collected from the maternal antecubital vein at 14:00 hr (daytime) and 02:00 hr (nighttime) during pregnancy, and also from the umbilical vein and artery immediately after delivery. Serum melatonin concentrations were measured by radioimmunoassay. Daytime serum melatonin levels in normal (single fetus; singleton) pregnancies were low. While the levels showed an increasing tendency toward the end of pregnancy, no statistically significant changes occurred. On the other hand, the nighttime serum melatonin levels increased after 24 weeks of gestation, with significantly (P < 0.01) high levels after 32 weeks; these values decreased to non-pregnant levels on the 2nd day of puerperium. Nighttime serum melatonin levels were significantly (P < 0.05) higher in twin pregnancies after 28 weeks of gestation than in singleton pregnancies, whereas the patients with severe preeclampsia showed significantly (P < 0.05) lower serum melatonin levels than the mild preeclampsia or the normal pregnant women after 32 weeks of gestation. Melatonin concentrations in umbilical vessels showed a higher tendency in neonates who were born during at night compared with the other neonates; moreover, those in the umbilical artery were generally higher than those in the umbilical vein. The present results indicate that in humans, the maternal serum melatonin levels show a diurnal rhythm, which increases until the end of pregnancy, reflecting some pathologic states of the feto-placental unit. Fetuses may produce melatonin with a circadian rhythm.     

Melatonin in patients with reduced REM sleep duration: two randomized controlled trials

Recent data suggest that melatonin may influence human physiology, including the sleep-wake cycle, in a time-dependent manner via the body's internal clock. Rapid-eye-movement (REM) sleep expression is strongly circadian modulated, and the impact of REM sleep on primary brain functions, metabolic processes, and immune system function has become increasingly clear over the past decade. In our study, we evaluated the effects of exogenous melatonin on disturbed REM sleep in humans. Fourteen consecutive outpatients (five women, nine men; mean age, 50 yr) with unselected neuropsychiatric sleep disorders and reduced REM sleep duration (25% or more below age norm according to diagnostic polysomnography) were included in two consecutive, randomized, double-blind, placebo-controlled, parallel design clinical trials. Patients received 3 mg melatonin daily, administered between 2200 and 2300 h for 4 wk. The results of the study show that melatonin was significantly more effective than placebo: patients on melatonin experienced significant increases in REM sleep percentage (baseline/melatonin, 14.7/17.8 vs. baseline/placebo, 14.3/12.0) and improvements in subjective measures of daytime dysfunction as well as clinical global impression score. Melatonin did not shift circadian phase or suppress temperature but did increase REM sleep continuity and promote decline in rectal temperature during sleep. These results were confirmed in patients who received melatonin in the second study (REM sleep percentage baseline/placebo/melatonin, 14.3/12.0/17.9). In patients who received melatonin in the first study and placebo in the second, the above mentioned effects outlasted the period of melatonin administration and diminished only slowly over time (REM sleep percentage baseline/melatonin/placebo, 14.7/17.8/16.2). Our findings show that exogenous melatonin, when administered at the appropriate time, seems to normalize circadian variation in human physiology. It may, therefore, have a strong impact on general health, especially in the elderly and in shift workers.     

Circadian rhythm of melatonin, corticosterone and phagocytosis: effect of stress

Melatonin has a functional connection with the immune system. Phagocyte function is altered by extirpation of the pineal gland, one source of melatonin, or by in vitro incubation of phagocytes with pharmacological concentrations of melatonin. Given that its synthesis by pinealocytes is under the control of the noradrenaline released by the sympathetic postganglionaric nerve endings, the present work was aimed at evaluating the circadian rhythm of melatonin, corticosterone, and phagocytosis in BALB/c mice in basal and stress situations. Peritoneal macrophages were used as phagocytes, latex beads as the particles to be ingested, and forced swimming to exhaustion as the stress situation. Radioimmunoassay was used to determine the animals' serum hormone levels. Samples were taken every 3 hr in the period from 04:00 to 22:00 hr, and every 30 min during the remaining period from 22:00 to 04:00 hr. Control mice presented a short-term melatonin peak at 23:30 hr, while the maximum inert-particle ingestion capacity of the peritoneal macrophages also occurred during the night but at 03:30 hr. The corticosterone levels in control mice presented a circadian rhythm with a day-time maximum peak (16:00 hr). Compared with the controls, the animals subjected to stress maintained, although at lower values, the melatonin peak at 23:30 hr, but they presented a loss of the rhythm of serum corticosterone levels, and the corticosterone levels and the macrophage phagocytic capacity were greater at all hours of the day.     

Melatonin stimulates glutathione peroxidase activity in human chorion

In preeclampsia, placental production of lipid peroxides is abnormally increased, while placental glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities are decreased. Administration of melatonin, a powerful scavenger of oxygen free radicals, also may protect the placenta from free radical-induced damage by increasing the activity of antioxidant enzymes. To test this hypothesis we administered melatonin to pregnant women before they underwent voluntary interruption of pregnancy between 7 and 9 wk of gestation. Melatonin (6 mg) was administered orally at 12:00 hr, and samples of chorion and maternal blood were obtained at the time of the procedure, 1, 2 or 3 hr later. We measured the melatonin concentration in maternal serum and activities of GSH-Px and SOD and levels of melatonin in chorionic homogenates. Melatonin administration was reflected by markedly increased melatonin concentrations in maternal serum and in chorion, with peak levels achieved 1 hr after melatonin administration (serum, 46.87 +/- 10.87 nM/L; chorionic homogenate, 4.36 +/- 1.56 pmol/mg protein). Between 1 and 3 hr after melatonin administration, GSH-Px activity in chorionic homogenates increased significantly (P < 0.001), with peak levels occurring at 3 hr (51.68 +/- 3.22 mU/mg protein per min, 137.3% of GSH-Px activity in untreated control subjects). No significant changes in chorionic SOD activity occurred during the 3-hr post-administration period. These results indicate that exogenous melatonin increases GSH-Px activity in the chorion and thereby may protect indirectly against free radical injury. Melatonin could be useful in treating preeclampsia and possibly other clinical states involving excessive free radical production, such as intrauterine fetal growth retardation and fetal hypoxia.     

Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels

Abstract:  The purpose of this study was to investigate the effects of melatonin on lipid metabolism in peri- and postmenopausal women. Forty-six women were enrolled in these studies. The relationship between night-time serum melatonin levels and serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol was investigated in 36 women. Night-time serum melatonin levels had a negative correlation with serum total cholesterol and LDL-cholesterol, and a loose positive correlation with HDL-cholesterol. To examine the effects of exogenous melatonin on lipid metabolism, serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were determined in 10 women before the onset of therapy and after 1 month of oral melatonin administration (1 mg melatonin daily). Melatonin administration significantly increased the serum levels of HDL-cholesterol. These results show that melatonin may influence cholesterol metabolism and suggest that the melatonin administration may become a new medical application for improvement of lipid metabolism and prevention of cardiovascular disease in peri- and postmenopausal women.     

Melatonin and the reduction or alleviation of stress.

In a double blind and placebo controlled study designed to investigate the effect of melatonin administration at 13:00 hr on menstrual characteristics, prolactin, and premenstrual syndrome-like symptoms during simulated eastward travel, it was noted that melatonin reduces or alleviates the stress associated with the simulated travel. Bright lights were utilized to simulate eastward movement across six time zones. Melatonin (10 mg) was given to healthy females for 5 consecutive days during the late follicular and early luteal phases of the menstrual cycle. Hourly blood samples, used for analysis of melatonin and prolactin levels, were obtained for 24 hr before entering the dose administration phase of the study and again on the last dose day. Volunteers also completed a profile of moods state questionnaire upon waking on each of 8 days which overlapped the in-house dose administration days. The placebo group showed a prolactin peak at 13:00 hr (dose time) on the last dose day/blood draw, while the melatonin group showed a prolactin peak at 15:00 hr. The prolactin peak at 13:00 hr is likely the result of stress, since stress is known to elicit the release of prolactin. The peak at 15:00 hr in the melatonin group was likely elicited by the administration of melatonin. Stress reduction in the melatonin group was supported by results from the profile of moods state questionnaire. The melatonin group consistently demonstrated scores indicative of less stress.     

Daytime melatonin and light independently affect human alertness and body temperature

Light significantly improves alertness during the night (Cajochen, Sleep Med Rev, 11, 2007 and 453; Ruger et al., AJP Regul Integr Comp Physiol, 290, 2005 and R1413), but results are less conclusive at daytime (Lok et al., J Biol Rhythms, 33, 2018 and 589). Melatonin and core body temperature levels at those times of day may contribute to differences in alerting effects of light. In this experiment, the combined effect of daytime exogenous melatonin administration and light intensity on alertness, body temperature, and skin temperature was studied. The goal was to assess whether (a) alerting effects of light are melatonin dependent, (b) soporific effects of melatonin are mediated via the thermoregulatory system, and (c) light can improve alertness after melatonin‐induced sleepiness during daytime. 10 subjects (5 females, 5 males) received melatonin (5 mg) in dim (10 lux) and, on a separate occasion, in bright polychromatic white light (2000 lux). In addition, they received placebo both under dim and bright light conditions. Subjects participated in all four conditions in a balanced order, yielding a balanced within‐subject design, lasting from noon to 04:00 pm . Alertness and performance were assessed half hourly, while body temperature and skin temperature were measured continuously. Saliva samples to detect melatonin concentrations were collected half hourly. Melatonin administration increased melatonin concentrations in all subjects. Subjective sleepiness and distal skin temperature increased after melatonin ingestion. Bright light exposure after melatonin administration did not change subjective alertness scores, but body temperature and proximal skin temperature increased, while distal skin temperature decreased. Light exposure did not significantly affect these parameters in the placebo condition. These results indicate that (a) exogenous melatonin administration during daytime increases subjective sleepiness, confirming a role for melatonin in sleepiness regulation, (b) bright light exposure after melatonin ingestion significantly affected thermoregulatory parameters without altering subjective sleepiness, therefore temperature changes seem nonessential for melatonin‐induced sleepiness, (c) subjective sleepiness was increased by melatonin ingestion, but bright light administration was not able to improve melatonin‐induced sleepiness feelings nor performance. Other (physiological) factors may therefore contribute to differences in alerting effects of light during daytime and nighttime.     

Seasonal variations in the nycthemeral rhythm of plasma melatonin in the camel (Camelus dromedarius)

Seasonal changes in the pattern of plasma melatonin were investigated in two groups of camels (Camelus dromedarius): 11 adult and six young camels. Animals were subjected to the outdoor conditions of a desert environment. Blood samples were taken at regular intervals of about 3 hr (added to particular samples at 1 hr before then 30 min and 1 hr after sunset, and 1 hr before and 1 hr after sunrise) for 24 hr at both solstices and equinoxes of the year. The plasma melatonin levels steeply increased soon after sunset and remained elevated throughout all the night. Then, melatonin concentrations progressively declined shortly before sunrise and returned to daytime basal levels 1 hr later. There was no seasonal variation in the amplitude or in the offset of the melatonin peak or in the daytime basal levels. The onset of the nocturnal peak was delayed by 2 hr in June at the summer solstice (P < 0.05), which can be related to the changes in night length between the two solstices. A significant effect of age was observed in all seasons. Melatonin levels were higher in the young camel group (fall equinox: P < 0.001; spring equinox: P < 0.01; winter solstice: P < 0.01; summer solstice: P < 0.05). The pattern of melatonin secretion in the camel showed a significant seasonal variation parallel to the photoperiodic changes of the year. The observed decline of melatonin levels during an extra-light pulse in the middle of the night indicates the light control of melatonin synthesis. It is not yet known if, in this low latitude desert region, the seasonal breeding period of the camel is cued by the photoperiod. The data obtained, however, clearly demonstrate that the camel has the capacity to follow and to integrate photoperiodic changes through melatonin changes.     

Seasonality of psychopathology and circannual melatonin rhythm

The association of seasonal changes in health and disease has been known for centuries. The prevalence of psychopathological symptoms with seasonal fluctuations and the use of melatonin as a biological marker of circadian and circannual rhythms is well documented. The aim of this work was to study the variability of melatonin secretion between summer and winter in our geographical area (28 degrees N, 16 degrees W) and relate the changes to the level of psychopathology. Ten drug-free, nonsmoker, healthy subjects were studied in summer (August) and winter (December). Blood samples for melatonin assays were collected every hour at night for 5 hr, from 22:00 to 02:00 hr, and next day at noon. Melatonin was assayed by an ELISA technique. Psychopathology was evaluated by means of the 28-item version of the General Health Questionnaire (GHQ-28). All subjects had a circadian rhythm of melatonin secretion in summer and winter. There was a seasonal rhythm with melatonin levels being significantly higher at night in winter than in summer. Melatonin levels at 22:00, 23:00, 24:00 and 01:00 hr and mean melatonin area under the curve (AUC) were significantly higher in winter than in summer. Melatonin AUC increased 80% in winter compared with summer. The GHQ-28 somatic and anxiety subscales and the total GHQ-28 score were significantly higher in winter than summer. Psychopathology scores were significantly and negatively correlated with melatonin production in summer and winter. Our data strongly suggest that melatonin production and psychopathology levels present seasonal fluctuations and these variations should be taken into account when conducting research in this field.     

Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset

In healthy young men, administration of a single light pulse (5000 lux for 3 hr) or a single melatonin pill (5 mg) at 20:40 hr under controlled constant routine conditions of <10 lux, yielded a phase delay and a phase advance, respectively, in the circadian marker of dim light melatonin onset 24 hr later. Phase shifts after combining the two interventions were additive. Melatonin suppression is not necessary for a phase shift by light, and melatonin is not a 'weak' Zeitgeber relative to bright light when ambient lighting is strictly controlled.     

A circadian rhythm of serum follicle-stimulating hormone in women.

While a nocturnal decline in serum LH levels in the early follicular phase of the menstrual cycle has been well established, a diurnal variation in serum FSH levels in women has not been demonstrated. We addressed this issue by determining serum LH and FSH levels at 15-min intervals for 24 h in the early follicular phase (EFP; n = 16) and late follicular phase (LFP; n = 10) of the menstrual cycle and in postmenopausal women (PMW; n = 10). Serum estradiol was simultaneously measured at hourly intervals. As expected, EFP, but not LFP and PMW, women had a 15% nocturnal decline (P less than 0.01) in transverse mean LH levels compared to values in the daytime hours. In contrast, nocturnal FSH transverse mean values were significantly lower than daytime values in all groups studied, demonstrating an 18% decline in EFP (P less than 0.001), a 17% decline in LFP (P less than 0.00001), and a 4.3% decline in PMW (P less than 0.01). Cosinor analysis revealed a circadian rhythm for FSH, with acrophases in the afternoon and nadirs at night in all three groups. The circadian amplitudes were 1.43 +/- 0.22, 1.02 +/- 0.16, and 8.42 +/- 1.31 IU/L for EFP, LFP, and PMW, respectively. The EFP nocturnal decline in LH did not conform to a cosine rhythm. A diurnal variation in estradiol was not present in any of the groups of women. These data constitute the first demonstration of a robust circadian rhythm of serum FSH in women. The comparable timing of the acrophase in all groups of subjects and its presence in the postmenopausal years suggest a central, rather than peripheral, feedback mechanism(s) for the circadian rhythmicity. This observation provides strong evidence for a dissociation in the hypothalamic regulation of pituitary LH and FSH secretion in women. The circadian peak and nadir of circulating FSH may prove to be determining for appropriate follicular development.